Association of Genetic Ancestry with Molecular Tumor Profiles in Colorectal Cancer

BackgroundPrior research on molecular correlates of disparities in incidence and outcomes of colorectal cancer (CRC) have typically used self-reported or observed categories of race and ethnicity, which can be missing or inaccurate. Furthermore, race and ethnicity do not always capture genetic similarity well, particularly in admixed populations. To overcome these limitations, we examined associations of CRC tumor molecular profiles using genetic ancestry. MethodsSequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8,454 CRC patients. Genetic ancestry proportions were estimated for five continental groups, Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS), using ancestry informative markers. We assessed association of genetic ancestry proportions and genetic ancestry-imputed race and ethnicity categories with somatic mutations in relevant CRC genes and in expression profiles, including consensus molecular subtypes (CMS). ResultsIncreased AFR ancestry was associated with higher odds of somatic mutations in APC, KRAS and PIK3CA and lower odds of BRAF mutations. Additionally, increased EAS ancestry was associated with lower odds of mutations in KRAS, EUR with higher odds in BRAF, and the Hispanic/Latino category with lower odds in BRAF. Greater AFR ancestry and the non-Hispanic Black category were associated with higher rates of CMS3, while patients in the Hispanic/Latino category had more indeterminate CMS. ConclusionsUse of genetic ancestry enables identification of molecular differences in CRC tumor mutation frequencies and gene expression that may underlie observed differences by race and ethnicity, and suggests that subtype classifications such as CMS may benefit from greater patient diversity.